Survival of organisms requires the ability to adapt to changes in the environment. Adaptation of oxidative metabolism is essential for meeting increased energy demands in response to stressors, such as exposure to cold temperatures or increased physical activity. Adaptive changes in metabolism are often achieved at the level of gene expression, and nuclear receptors have prevalent roles in mediating such responses. Estrogen-related receptor ␣ (ERR␣) was the first orphan nuclear receptor to be identified, and yet its physiologic function remains unknown. Here, we show that mice lacking ERR␣ are unable to maintain body temperature when exposed to cold. Surprisingly, the inability to adapt to cold is not due to defects in the acute transcriptional induction of genes important for thermogenesis. Rather, we show that ERR␣ is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue (BAT), and thus for providing the energy necessary for thermogenesis. ERR␣ fulfills this role by acting directly at genes important for mitochondrial function, parallel to other factors controlling mitochondrial gene expression, such as NRF1 and NRF2/GABPA. Our findings demonstrate that ERR␣ is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis.mitochondrial biogenesis ͉ oxidative metabolism ͉ brown adipose tissue E lucidation of the physiologic roles of many nuclear receptor family members has not only revealed their importance in regulating aspects of metabolism but also suggested strategies by which synthetic ligands to such receptors [e.g., peroxisome proliferator-activated receptors (PPARs) or liver X receptor (LXRs)] can impact the treatment of metabolic disease (1). Estrogen-related receptor (ERR) ␣ is an orphan nuclear receptor and the founding member of the small subfamily of EstrogenRelated Receptors, which includes also ERR␤ and ERR␥ (2-4). Even though progress has been made in identifying cellular pathways regulated by ERR␣, the physiologic responses to which ERR␣ function contributes remain largely unknown (5-8).ERR␣ function has been linked to at least three pathways: estrogen signaling, bone formation and oxidative metabolism (reviewed in refs. 4, 9, and 10). Several lines of evidence support an ERR␣ role in oxidative metabolism. First, ERR␣ expression is high in tissues with high oxidative capacity (2, 11) and increased at physiologic states of increased energy demand, such as fasting, exposure to cold or exercise (12)(13)(14). Second, ERR␣ activity is regulated by the peroxisome proliferator-activated receptor ␥ coactivators (PGC)-1␣ and PGC-1␤ (13, 15, 16), which coordinate the expression of genes involved in mitochondrial biogenesis and oxidative metabolism (reviewed in refs. 17 and 18). Third, inhibition of ERR␣ in cultured cells diminishes the ability of PGC-1␣ to induce mitochondrial biogenesis and cellular respiration (6, 7). Conversely, constitutively active ERR␣ induces mitochondrial biogenesis and...

Brief exposure of rodents to estrogens during early development alters prostate branching morphogenesis and cellular differentiation in a dose-dependant manner. If estrogenic exposures are high, these disturbances lead to permanent imprints of the prostate, which include reduced growth, differentiation defects of the epithelial cells, altered secretory function and reduced responsiveness to androgens in adulthood. This process, referred to as neonatal imprinting or developmental estrogenization, is associated with an increased incidence of prostatic lesions with aging, which include hyperplasia, inflammation and dysplasia. To better understand how early estrogenic exposures can permanently alter prostate growth and function and predispose the gland to neoplasia, the effects of estrogens on prostatic steroid receptors, cell-cell communication molecules and key developmental genes were examined. Transient and permanent alterations in the expression of prostatic androgen receptors, estrogen receptors alpha (ERalpha) and beta, and retinoic acid receptors are observed. It is proposed that the estrogen-induced alterations in these critical transcription factors play a fundamental role in initiating prostatic growth and differentiation defects. Down-stream effects of the altered steroid receptor expression include disruption of TGFbeta paracrine communication, altered expression of gap junction connexin molecules and loss of epithelial cadherin on epithelial cells. Additionally, specific disruptions in the expression of prostatic developmental genes are observed in response to neonatal estrogen. An extended developmental period of hoxa-13 expression, a lack of hoxd-13 increase with maturation, and an immediate and sustained suppression of hoxb-13 was noted within prostatic tissue. A transient decrease in Nkx3.1 expression in the developing prostate was also observed. Thus subtle and overt alterations in Hox-13 and Nkx3.1 genes may be involved in the altered prostate phenotype in response to neonatal estrogen exposure. In summary, estrogen imprinting of the prostate gland is mediated through up-regulated levels of stromal ERalpha, which initiates alterations in steroid receptor expression within the developing gland. Rather than being an androgen-dominated process, as occurs normally, prostatic development is regulated by alternate steroids, including estrogens and retinoids, in the estrogenized animal. This, in turn, leads to disruptions in the coordinated expression of critical developmental genes including TGFbeta, Hox-13 genes and Nkx3.1. Since a precise temporal expression pattern of these and other molecules is normally required for appropriate differentiation of the prostatic epithelium and stroma, the estrogen-initiated disruption in this pattern would lead to permanent differentiation defects of the prostate gland. It is hypothesized that these molecular and cellular changes initiated early in life predispose the prostate to the neoplastic state upon aging.

Findings from this study indicate the importance of work-to-family conflict to nurse turnover. While work setting has a strong, well-documented influence on job satisfaction, limiting job satisfaction efforts to work setting improvements may not yield the hoped-for results unless work-to-family conflict is also considered and addressed.

A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids, suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.

Title. The efficacy of reflexology: systematic review. Aim. This paper is a report of a systematic review to evaluate the efficacy of reflexology in any condition. Background. Anecdotal evidence has shown potential benefits of reflexology in a variety of health conditions. However, the efficacy of reflexology has yet to be determined. Data sources. Cochrane library, PubMed, MEDLINE, EBM review, ProQuest Medical Bundle and SCOPUS databases were searched using the following medical subject headings or key words: reflexology, foot reflexotherapy, reflexological treatment, foot massage and zone therapy. Chinese articles were searched through the Chinese electronic periodical services and Wangfane database. The publication date was limited from 1996 to 2007. Review methods. Studies were selected if they were written in English or Chinese, used a controlled clinical trial design, used reflexology as a stand-alone modality, and reported such outcomes as symptoms relief, quality of life and patients' perceptions of reflexology. Study quality was reviewed based on the evidence rating system of the United States Preventive Services Task Force, and studies with the evidence rating of II-2 fair or above were included in this review. Results. Among the five studies suitable for review, there was only one report of a statistically significant treatment effect. Among the 12 outcome variables examined, the treatment effect size for urinary symptoms was large, whereas the effect size for other conditions was negligible.Conclusion. There is no evidence for any specific effect of reflexology in any conditions, with the exception of urinary symptoms associated with multiple sclerosis. Routine provision of reflexology is therefore not recommended.